PIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas

British Journal of Cancer
Jonathan BlackAlessandro D Santin

Abstract

We evaluated the role of PIK3CA-mutations as mechanism of resistance to trastuzumab in primary HER2/neu-amplified uterine-serous-carcinoma (USC) cell lines. Fifteen whole-exome-sequenced USC cell lines were tested for HER2/neu-amplification and PIK3CA-mutations. Four HER2/neu-amplified USC (2-harbouring wild-type-PIK3CA-genes and 2-harbouring oncogenic-PIK3CA-mutations) were evaluated in in vitro dose-titration-proliferation-assays, cell-viability and HER2 and S6-protein-phosphorylation after exposure to trastuzumab. USC harbouring wild-type-PIK3CA were transfected with plasmids encoding oncogenic PIK3CA-mutations (i.e., H1047R/R93Q) and exposed to trastuzumab. Finally, trastuzumab efficacy was tested by using two USC xenograft mouse models. Seven out of fifteen (46%) of the USC cell lines were HER2/neu-amplified by fluorescence in situ hybridisation. Within these tumours four out of seven (57%) were found to harbour oncogenic PIK3CA-mutations vs two out of eight (25%) of the HER2/neu not amplified cell lines (P=0.01). HER2/neu-amplified/PIK3CA-mutated USC were highly resistant to trastuzumab when compared with HER2/neu-amplified/wild-type-PIK3CA cell lines (P=0.02). HER2/neu-amplified/PIK3CA wild-type cell lines transfected wi...Continue Reading

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Citations

Feb 28, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Ebubekir DiricanAyşe Özer
Oct 4, 2015·Gynecologic Oncology·Amy Bregar, Whitfield Growdon
Aug 15, 2018·International Journal of Molecular Sciences·Michiel Remmerie, Veerle Janssens
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Jan 12, 2019·Gynecologic Oncology·Elena BonazzoliAlessandro D Santin

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Methods Mentioned

BETA
biopsies
flow cytometry
Protein Assay
transfection
xenograft
exome sequencing
xenografts

Clinical Trials Mentioned

NCT01367002

Software Mentioned

GraphPad
Cell Quest
GraphPad Prism5

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